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Interregional Seminar for Quality Control Laboratories involved in WHO Prequalification Programme and/or participating in respective sampling
and testing projects, Nairobi, Kenya, 23-25 September 2009
WHO sampling guideline - Introduction
Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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Before sampling
I. purpose of sampling?
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Sampling process
II.Sampling operation
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I - Preparation for sampling
Sampling tools should be available to the sampler, e.g. to open containers (knives, hammers,...),
material to reclose the packages (sealing tape), self-adhesive labels to indicate that some of the
contents have been removed, etc...
Sampling tools should be made of inert materials (e.g. polypropylene or stainless steel; avoid
glass) and kept very clean. After use, thoroughly washed, rinsed with water or suitable solvent,
dried and stored in clean conditions.
Washing facilities should be located in, or close to, the sampling area.
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Examples of types of sampling tools (Appendix 1 of WHO guideline)
Dip tubes
Spatulas for liquids
for solids Sample thieves
for solid samples in
deep containers
Bag-sampling
spears for taking
samples from bags
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II - Sampling operation
Sampling plan: description of the location, number of units and/or quantity of material that
should be collected, and associated acceptance criteria.
Make sure that representative samples are taken in sufficient quantity. Representative
sample: sample obtained according to a sampling procedure designed to ensure that the
different parts of a batch or the different properties of a non-uniform material are
proportionately represented.
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II - Sampling operation (cont.)
Sampling operations should be supervised and documented => sample collection form
=> always kept together with the collected sample.
Sample collection form: written record of the sampling operations, containing: batch
number, sampling date/place, reference to sampling protocol used, description of
containers and materials sampled, possible abnormalities, any relevant observations,
name/signature of the sampler...
Store the sample in a properly labelled container: sample type, name of material,
identification code, batch number, code, quantity, date of sampling, storage conditions,
handling precautions, container number....
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Example of sample collection form
(Appendix 2 of WHO guideline)
Page 1 Page 2
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II - Sampling operation (cont.)
Pay attention to any signs of non-uniformity of the material:
Differences in shape, size, colour of particles in crystalline/granular/powdered subst.
Moist crusts on hygroscopic substances.
Solid deposits in liquids or semi-liquids.
Stratification of liquids.
In this case, sample portions of the material and test them separately from the material
with normal aspect.
Take into account previous experience with the product and supplier.
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III Sample storage and retention
Containers
Containers used to store a sample should comply with the storage directions for
the active pharmaceutical ingredient, excipient or drug product:
should not interact with the sampled material.
should not allow contamination.
should protect the sample from light, air and moisture.
should be sealed and adequately labelled.
avoid mix-up when containers are opened (screw caps, separate lids).
manipulations/unauthorised opening should be easy detectable.
transported in such way as to avoid breakage.
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III Sample storage and retention (cont.)
Security and adequate storage conditions (light, ventilation, safety requirements, and
any special requirements) should be ensured for the rooms in which samples are
stored.
Samples should be stored according to the storage conditions as specified for the
respective API, excipient or drug product.
Packaging materials similar to those in which the bulk is supplied should be used for
long-term storage.
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Examples of types of containers used to store samples of starting materials and
bulk products (Appendix 4 of WHO guideline)
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Sampling for regulatory issues
I. Drug quality surveillance programmes
II. Inspections
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I - Drug quality surveillance programmes
The extent of the routine surveillance programmes for drug quality, carried out by
National Drug Regulatory Authorities will depend on:
capacity of the national drug QC lab
extent to which the quality of the product has been assessed prior to registration
extent to which the requirements for GMP are implemented
number of products imported from abroad
The programme should include marketed products, whether registered for sale or
prepared in pharmacies.
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I - Drug quality surveillance programmes (cont.)
The responsible laboratory should prepare the sampling programme (if needed
under the guidance of the drug regulatory authority) every year or half a year.
Sampling programme:
Lists the products to be sampled during a given period
Specifies the sampling procedure
Specifies the size of the samples to be collected (including retention sample)
States to what extent each brand of a given product will be sampled
States which local authority or inspector will be responsible for sampling
Indicates to which laboratory each sample should be sent (if more than 1)
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II - Inspections
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Sampling for acceptance
I. Starting materials
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I Sampling of starting materials
Non-uniform material:
Special sampling tools are needed.
Alternatively, if applicable, restore uniformity before sampling (e.g. stratified
liquid may be stirred or a solid deposit in a liquid may be dissolved by gently
warming and stirring) validated method !
In these cases, in order to prepare representative samples, see ISO 2859.
Partially processed natural products (animal, herbal and mineral) should be
treated as intrinsically non-uniform. For info, sampling of herbal drugs, see
European Pharmacopoeia chapter 2.8.20.
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II - Sampling of intermediates in manufacturing and
bulk products
Intermediates: liquids and semi-solid products; powdered solids or
granulates; unit dosages forms in bulk (tablets, capsules).
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WHO Certification Scheme for Products moving in International Commerce
is an international voluntary agreement, created to enable countries with
limited drug regulatory capacity to obtain partial assurance from exporting
countries concerning the safety, quality and efficacy of the products they plan
to import.
http://www.who.int/medicines/areas/quality_safety/regulation_legislation/certification/en/
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III - Sampling of finished products
Uniformity : a single consignment* of a product from a single manufacturer and labelled
with a single batch number may be assumed to be uniform.
The minimum size of the samples to be taken is determined by the requirements of the
analytical procedure used to test the product (tests of unit dosage forms for uniformity
of weight, volume or content, or sterility tests can require a large number of samples).
Sampling and testing may be adjusted according to the experience with the source of
the product, e.g. manufacturer or supplier.
*Consignment: quantity of a bulk starting material or drug product, made by one manufacturer or supplied by one agent,
supplied at one time in response to a particular request (1 or more containers, 1 or more batches).
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IV - Sampling of packaging materials
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IV - Sampling of packaging materials (cont.)
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Sampling plans
I.Starting materials
II.Finished products
III.Packaging materials
Note: guideline primarily addressed to Drug Regulatory Authorities, these sampling plans
might not be appropriate for manufacturers.
The following plans are examples
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Sampling plans for starting materials
I.n-plan
II.p-plan
III. r-plan
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I The n-plan
Only used when material is considered uniform and from a recognised source.
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NOTES:
The n-plan is NOT statistically based and should be used only as a guiding
principle.
The n-plan is NOT recommended for use by control laboratories of
manufacturers that are required to analyse and release or reject each received
consignment of the starting materials used to produce a drug product.
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II The p-plan
May be used when material is considered uniform, from a recognised source and the main
purpose is to test for identity.
p 0.4 N
N = sampling units in the consignment (e.g.
individual package, drum or container)
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III The r-plan
May be used when material is considered non-uniform and/or obtained from a not
well know source.
Can be used for herbal medicinal products used as starting materials.
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Sampling plans for packaging materials
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Sampling plans for finished products
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ISO 2859 series - Sampling procedures for inspection by attributes
ISO 2859-2:1985 - Part 2: Sampling plans indexed by limiting quality (LQ) for isolated
lot inspection
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Practical example
http://www.ages.at
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Step 1: Sampling order from a scientific advisor
Step 2: Verification and authorization of order
Step 3: Assignment to authorized sampling staff
1: ordering department
2: date / name of scientific advisor
3: urgent / planned beginning of
1 4
2 5
analysis
3 6
4: requested sampling site
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Step 4: Sampling
request sent by fax
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sampling performed onsite
Part 1
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Part 2
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Step 5: Arrival of sample
3
4
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References
WHO guidelines for sampling of pharmaceutical products and related materials. Annex 4 of
WHO Technical Report Series No. 929 (2005).
ISO 10725:2000 - Acceptance sampling plans and procedures for the inspection of bulk materials.
Good Manufacturing Practices; Part I - Basic Requirements for Medicinal Products ; Part II - Basic
Requirements for Active Substances used as Starting Materials.
European Pharmacopoeia. Chapter 2.8.20. Herbal drugs: sampling and sample preparation.
ANSI/ASQ Z1.4-2008 Standard (American National Standards Institute/American Society for Quality)
- Sampling Procedures and Tables for Inspection by Attributes.
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http://www.edqm.eu
Marta Miquel
Scientific Officer
Council of Europe
European Directorate for the Quality of Medicines and HealthCare (EDQM)
Biological Standardisation, OMCL Network & HealthCare Department (DBO)
7 Alle Kastner, CS 30026
F- 67081 Strasbourg, France
Tel.: + 33 (0) 3 90 21 42 41
Fax: + 33 (0) 3 88 41 27 71
E-mail: marta.miquel@edqm.eu
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